title: Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling.
abstract: Premature senescence is a key process in the progression of diabetic nephropathy (DN). In our study, we hypothesized that receptors for advanced glycation end-products (RAGE) mediate endoplasmic reticulum (ER) stress to induce premature senescence via p21 signaling activation in diabetic nephropathy. Here, we demonstrated that elevated expression of RAGE, ER stress marker glucose-regulated protein 78 (GRP78), and cell-cycle regulator p21 was all positively correlated with enhanced senescence-associated-β-galactosidase (SA-β-gal) activity in DN patients. In addition, the fraction of SA-β-gal or cells in the G0G1 phase were enhanced in cultured mouse proximal tubular epithelial cells (PTECs) and the expression of RAGE, GRP78 and p21 was up-regulated by advanced glycation end-products (AGEs) in a dose- and time-dependent manner. Interestingly, ER stress inducers or RAGE overexpression mimicked AGEs induced-premature senescence, and this was significantly suppressed by p21 gene silencing. However, RAGE blocking successfully attenuated AGEs-induced ER stress and p21 expression, as well as premature senescence. Moreover, ER stress inducers directly caused p21 activation, premature senescence, and also enhanced RAGE expression by positive feedback. These observations suggest that RAGE promotes premature senescence of PTECs by activation of ER stress-dependent p21 signaling.
authors.affiliation: Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing 400042, China; Kidney Center and Key Laboratory of the People's Liberation Army, Chinese PLA General Hospital and Military Medical Postgraduate College, Beijing 100853, China; Dazhou Military Hospital of Chinese PLA, Dazhou, Sichuan, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.forename: Guang-Yan
authors.initials: GY
authors.lastname: Cai
authors.forename: Xiang-Mei
authors.initials: XM
authors.lastname: Chen
authors.forename: Ju-Rong
authors.initials: JR
authors.lastname: Yang
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Lin
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Ben-Gang
authors.initials: BG
authors.lastname: Huo
authors.forename: Jun
authors.initials: J
authors.lastname: Zhan
authors.forename: Ya-Ni
authors.initials: YN
authors.lastname: He
mesh_terms: D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D025461:Feedback, Physiological / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000494:pharmacology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D051379:Mice; D008875:Middle Aged; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D000091342:Endoplasmic Reticulum Chaperone BiP; D017127:Glycation End Products, Advanced; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic
keywords: 4-PBA; 4-phenylbutyrate; 4′,6-diamidino-2-phenylindole; AGEs; BSA; DAPI; DN; Diabetic nephropathy; ER; ER stress; GFP; GRP78; Green fluorescent protein; MOI; PTECs; Premature senescence; RAGE; SA-β-gal; SAHF; TG; TM; advanced glycation end-products; bovine serum albumin; diabetic nephropathy; endoplasmic reticulum; glucose-regulated protein 78; multiplicity of infection; p21; proximal tubular epithelial cells; receptor for advanced glycation end-products; senescence-associated heterochromatic foci; senescence-associated-β-galactosidase; thapsigargin; tunicamycin